Dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzene

ABSTRACT

The dialkylaminoalkyl ethers of 2-alkoxy-3,5-dihalobenzene of this invention are effective in the treatment of mammals afflicted with convulsions, pain, excessive histamine or hypotension. The compounds are relatively non-toxic in dosages required to alleviate such conditions.

United States Patent Thominet Sept; 9, 1975 DIALKYLAMINOALKYL ETHERS OF [58] Field of Search 260/247.7 C, 570.7

Z-ALKOXY-3,5-DIHALOBENZENE v [75] Inventor: Michel Leon Thominet, Paris, [56] References Cited France UNITED STATES PATENTS 7 Assignee; Societe dEtudes scientifiques et 2,967,201 1/1961 Soper 260/570.7 lndustrienes de l,ne de France, 3,235,597 2/1966 Mills et a] 260/570.5 Paris, France OTHER PUBLICATIONS [22] Filed: June 13, 1973 Abood, Arch. int. Pharmacodlyn, 196i, 134 No. 1-2

. 106-130. 211 Appl. 110.; 369,567 pp Related US. Application Data Primary Examiner-Robert Gerstl [63] Continuation-impart of Ser. No. 80,211, Oct. 12, Assistant Examiner-REM y 1970, abandoned, which is a continuation-in-part of Attorney, g or ra Nolan Ser. No. 798,164, Feb. 10, 1969, abandoned.

ABSTRACT [30] P The dialkylaminoalkyl ethers of 2-alkoxy-3,5-

Feb. 16,1968 France 68.l40294 dihalobenzene of this invention are effective in the May 10, 1968 France 68.151632 treatment of mammals afflicted with convubions,

pain, excessive histamine or hypotension. The com- [52] Cl 260/ 24717 s; 260/247'2 R; pounds are relatively non-toxic in dosages required to alleviate such conditions. 260/326.5 M; 260/567.6 M; 260/570.7;

424/248; 424/32 5 7 Claims, N0 Drawings [5]] Int. Cl. C07C 93/06; C07D 295/00 DIALKYLAMINOALKYL ETHERS OF 2-ALKOXY-3,S-DIHALOBENZENE This application is a continuation-in-part of the copending US. patent application of M. L. Thominet, Ser. No. 80,211, filed Oct. 12, 1970, now abandoned. The application Ser. No. 80,211 is a continuation-inpart of the US. patent application Ser. No. 798,164, filed Feb. 10, 1969, now abandoned.

This invention relates to dialkylaminoalkyl ethers of 2-alkoxy-3,S-dihalobenzene, their non-toxic acidaddition salts with a mineral or organic acid, their nontoxic quaternary ammonium salts and the process of producing these compounds. These compounds have significant pharmacological properties, particularly as spasmogenic agents and are adapted for the treatment of mammals with them.

The dialkylaminoalkyl ethers of the invention have the formula:

in which m is an integer from through 2 and n is an integer from 0 through 2; R and R are hydrogen or lower alkyl of less than 6 carbon atoms; R and R are hydrogen, lower alkyl of less than 6 carbon atoms or form a five or six membered heterocyclic radical; and X and Y are halogens.

Examples of lower alkyl having less than 6 carbon atoms are methyl, ethyl, propyl, isobutyl and amyl. Ex amples of five or six membered heterocyclic radicals are pyrrolidyl, piperidyl, morpholyl, piperazinyl, nalkylpiperidyl and imidazolyl. The halogens X and Y may be the same or different; for example, they may be fluorine, chlorine or bromine.

The acid addition salts of the dialkylaminoalkyl ethers of 2-alkoxy-3,S-dihalobenzene are those produced by reacting the base with a mineral or organic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, citric acid, tartaric acid, or ethane sulfonic acid. The quaternary ammonium salts may be obtained by reacting the benzamide with an aliphatic or aromatic alkylating agent, such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, methyl benzene sulfonate, methyl p-toluene sulfonate, ethyl bromide, propyl bromide or benzyl chloride.

The dialkylaminoalkyl ethers of 2-alkoxy-3,5- dihalobenzene amides of this invention are produced by acetylating a monoether of pyrocatechol, then halogenating the compound obtained, then deacetylating the compound and treating it with an alkylaminoalkyl I Chloride.

A more comprehensive understanding of this invention is obtained by reference to the following examples:

EXAMPLE I (2'-D1ETHYLAMINOETHOXY )-2METHOXY-3 ,5- DICHLOROBENZENE HYDROCHLORIDE STAGE A: 3,5-dichloroguaiacol 62 g of guaiacol (0.5 mole) is acetylated in a 250 ml balloon flask provided with a reflux condenser by means of acetic anhydride, in the presence of a few drops of concentrated sulfuric acid. When the reaction is concluded, the sulfuric acid is neutralized with sodium acetate and then, when the solution has been cooled, the guaiacol acetate is chlorinated.

The above solution is placed in a one litre balloon flask provided with an agitator and a thermometer. ml of acetic acid is then added. g of chlorosuccinimide is then added in small quantities. The suspension is then heateed to from 50 to 55C and is then kept in an oven at 55C for 1 17 hours.

When the reaction is complete, cooling is effected and two litres of water is added with agitation being maintained. The chlorinated derivative crystallizes. It is dried without heating, washed and deacetylated by means of 125 m1 of 30% soda lye. The product is distiled and then recrystallized from petroleum ether. 66 g of 3,5-dichloroguaiacol is obtained (melting point: 62 to 62C) (yield 68%) STAGE B: (2'-diethylaminoethoxy )-2-methoxy-3 ,5- dichlorobenzene 50 g of 3,5-dichloroguaiacol (0.25 mole) is poured into a solution of sodium ethylate prepared from 6 g of sodium in 78 ml. of absolute alcohol. 7

39 g (0.26 mole 10% excess) of 1-diethylamino-2- chloroethane is added to the red solution obtained.

Upon gentle heating, the solution becomes cloudy. Sodium chloride precipitates. Heating under reflux is then applied for 7 hours. Cooling is effected and then 300 ml of water and 25 ml of concentrated hydrochloric acid are added. The aqueous solution is filtered, treated with black and the base is precipitated by 40 ml of ammonia and extracted with ether. After distillation of the ether, 51 g (yield: 72%) of (2'- diethylaminoethoxy)-2-methoxy-3,S-dichlorobenzene is obtained (boiling point/7 mm: to 166C).

STAGE c (2'-diethylaminoethoxy)-2meth0xy-3,5- dichlorobenzene hydrochloride The base prepared above is dissolved in 100 ml of acetone and 6 g 35 of dry hydrochloric acid in 20 ml of acetone is added. (2'-diethylaminoethoxy)-2-methoxy- 3,5-dichlorobenzene hydrochloride precipitates, which is then dried without heating, washed with aceton and then dried. 51' g of the product is obtained (melting point: 132 to 134C).

ANALYSIS. Calculated 70: C, 47.49; H, 6.09; Cl, 32.42; N, 4.26. Actual C,47.31; H, 6.14; Cl, 32.24; N, 4.18.

EXAMPLE I1 3-DIMETHYLAM1NOPROPOXY)-2-METHOXY- 3,5-DICHLOROBENZENE HYDROCHLORIDE Stage A is similar to that described in Example 1.

STAGE B: (3 -dimethyla'minopropoxy )-2-methoxy-3 ,5- dichlorobenzene 63 g of 3,5-dichloroguaiacol (0.32 mole) is poured into a solution of sodium ethylate obtained from 7.5 g of sodium and 100 ml of ethyl alcohol. 44 g (0.326 mole excess) of l-dimethylamino-3- chloropropane is added and the resulting mixture is heated under reflux for 6 hours. Precipitation of sodium chloride is observed. It is cooled and dissolved in 300 ml of water and 30 ml of concentrated hydrochloric acid. The aqueous solution is treated with black. The resulting base is precipitated by adding ammonia. It is extracted with ether, then the ether is removed and the residue is distilled.

63 g (yield 70%) of (3'-dimethylaminopropoxy)-2- methoxy-3,5-dichlorobenzene is obtained (boiling point/ mm: 190 to 195C).

I STAGE C: (3 -dimethylaminopropoxy )-2-methoxy-3 ,5- dichlorobenzene hydrochloride EXAMPLE III (3 -DIETHYLAMINOPROPOXY )-2-METHOXY 3,5'DICHLOROBENZENE HYDROCHLORIDE Stage A is similar to that described in Example I.

- STAGE B: (.3 '-diethylaminopropoxy )-2-methoxy-3 ,5- dichlorobenzene The 66 g of 3,5-dichloroguaiacol (0.34 mole) prepared above is added to a solution of sodium ethylate prepared from 7 g of sodium and 130 ml of absolute alcohol. 55 g of diethylamino-3-chloropropane (0.34 mole 10% excess) is added to the resulting red solution.

Gentle heating is applied; after 5 minutes, the solution becomes cloudy. Sodium chloride precipitates. Heating under reflux is then applied for 2 hours.

Cooling is effected and water is added. The amine precipitates. The mixture is decanted and extracted a number of times with methylene chloride, then the organic solution is washed by means of a 4% sodium solution and then with water. It is dried over potassium carbonate and the solvent is distilled. 96 g of (3- diethylaminopropoxy)-2-methoxy-3,5- dichlorobenzene is obtained. (yield: 95%) STAGE C: (3 -diethylaminopropoxy )-2-methoxy-3,5- dichlorobenzene hydrochloride The base prepared above is dissolved in twice its weight of acetone.

Dry hydrochloric acid is bubbled into the same volume of acetone and this solution is poured into the base until methyl red changes Color. The hydrochloride crysytallizes. It is dried without heating, washed. dried in the air and then in an oven at 30C. It is recrystallized a number of times from isopropanol. 51 g of (3- diethylaminopropoxy )-2-methoxy-3 ,5- v dichlorobenzene hydrochloride is obtained (melting point: 142C) (yield: 48%).

ANALYSIS. Calculated C, 49.05; H, 6.42; CI, 31.09; N, 4.09.Actual C,49. 16; H, 6.46; CI, 30.90; N, 4.19.

EXAMPLE IV (3 -MORPHOLINOPROPOXY )-2-METHOXY-3,5-

DICHLOROBENZENE HYDROCHLORIDE Stage A is similar to that described in Example I.

STAGE B: y (3 -morpholinopropoxy 2-methoxy-3 ,5- dichlorobenzene 54 g of 3,5-dichloroguaiacol (0.28 mole) is added to sodium ethylate produced by reacting 6.44 g of sodium on 84 ml of ethyl alcohol. 51 g (0.28 mole 10% excess) of l-chloro-3-morpholinopropane is added to the resulting solution. The mixture is heated under reflux for 8 hours. Precipitation of sodium chloride is observed. Cooling is effected and then the mixture is dissolved in 300 ml of water and 30 ml of concentrated hydrochloric acid. The resulting solution is filtered, then ammonia is added to precipitate the base which is extracted with ether. The ether is eliminated and the residue is distilled under vacuum.

73 g (yield: 82%) of (3-morpholinopropoxy)-2- methoxy-3,S-dichlorobenzene is obtained (boiling point/ 16 mm: 197 to 200C).

STAGE C: (3-morpholinopropoxy)-2-methoxy-3,5- dichlorobenzene hydrochloride The base prepared above is dissolved in 150 ml of acetone. 8.32 g of dry hydrochloric acid dissolved in 50 ml of acetone is added; (3-morpholinopropoxy)-2- methoxy-3,5-dichlorobenzene hydrochloride precipitates, which is dried without heating, washed on a filter with acetone and dried. (Weight: 73 g) (Yield: 94%) (Melting point: 183 to 184C).

ANALYSIS. Calculated C, 47.12; H, 5.61; C], 29.87; N, 3.93. Actual C,47.33; H, 5.72; CI, 29.77; N, 3.92.

EXAMPLE V (3DIETHYLAMINOISOPROPOXY )-2-METHOXY- 3,5-DICI-ILOROBEI IZEI IE OXALATE Stage A is similar to that described in Example 1.

STAGE B: (3-diethylaminoisopropoxy )-2-methoxy-3 ,5-

' dichlorobenzene 63 g of 3,5-dichloroguaiacol (0.326 mole) is added to sodium ethylate which is prepared by dissolving 7.5 g of sodium in ml of alcohol. There is added to the resulting solution 54 g (0.326 mole 10% excess) of fi-chloropropyl diethylamine. The mixture is heated for 7 hours, sodium chloride precipitates. It is dissolved with 300 ml of water and 4.5 ml of concentrated hydrochloric acid. The solution is filtered and 60 ml of ammonia is added. The precipitated base is extracted with ether. The ether is eliminated and the residue is distilled.

70 g (yield: 7 to 10%) of (3- diethylaminoisopropoxy)-3,5-dichlorobenzene is obtained (boiling point/ 5 mm: 166 to 167C).

STAGE C: (3 '-diethylaminoisopropoxy )-2-methoxy-3,5- dichlorobenzene oxalate The base prepared above is dissolved in 130 ml of absolute alcohol; 21 g of oxalic acid which is previously dissolved in 40 ml of alcohol is added. diethylaminoisopropoxy )-2-methoxy-3 .5 dichlorobenzene oxalate precipitates, which is dried without heating, washed with alcohol and dried. (Melting point: 128C).

ANALYSIS. Calculated C, 48.48; H, 5.81; Cl, 17.93; N, 3.53. Actual C, 48.28; H, 5.98; Cl, 17.80; N, 3.39.

EXAMPLE Vi (3 -DIETHYLAMINOPROPOXY )-2-METHOXY- 3 ,S-DICHLOROBENZENE BROMOMETHYLATE The base is prepared as described in Stages A and B of Example Ill.

A methanolic solutin of methyl bromide (18 g of Br CH, for 161 ml of solution, i.e. 0.17 mole 10% excess) is poured into 51 g (0.17 mole) of (3- diethylaminopropoxy )-2-methoxy-3 ,5- dichlorobenzene dissolved in 100 ml of methanol. The

solution is maintained at ambient temperature for about 90 hours. The alcohol is distilled under vacuum until a constant weight is reached. The resulting product is recrystallized from acetone. The crystals are dried without heating, washed with acetone and dried at 55C. 43 g of white crystals of (3'- diethylaminopropoxy)-2-methoxy-3,5- dichlorobenzene bromomethylate is obtained. This product is very hygroscopic. (Melting point: 114 to 115C) (Yield: 63%) ANALYSIS. Calculated C, 44.89; H, 5.98; Br, 19.95; C1, 17.70; N, 3.49. Actual C,44.76; H, 6.10; Br, 20.03; Cl, 17.56; N. 3.28.

The high degrees of toxicity, studied on mice, have shown that the compounds, subject of the present intherapeutic use. The following table is given by way of example:

D.l.. 50 in mg/kg COMPOUND Compound in base form lV 1P SC PO (3'-dicthylamiriopropoxy)-2- 34.8 [81 608 737 methoxy-3,5 dichlorobenzene 31.3 v

l. The spasmogenic action of the compounds of the invention was studied on detachedguinea-pig ileum.

Taking a section of detached guinea-pig ileum, the severity of the contractions caused by increasing doses of the product under study, namely 0.1 rig/ml 0.2

,ug/ml 0.4 ,ug/ml, is measured.

This study revealed the powerful spasmogenic properties of the medicaments of the invention.

2. The atropine counteracting action was also studied on detached guinea-pig ileum.

. graphic determination of the counteracting dose 50.

vention, are ofa toxicity which is quite compatible with 45 to the 40 t3-diethylaminopropoxy)-2mcthoxy-3.5-dichlorohenzene. and acctylcholine.

Atropine Spasmogcnic Agents Mean Counteracting Dose 50 in Lg/ml (3'-dicthylaminopropoxy)-2- methoxy-3,S-dichlorobenzenc 1.9 (a) Spasmogenic dose:

2.10 Acetylcholinc i.i0- 0.010 (a) (a) Determined over 12 tests. each section of ileum being successively subjected spasmegenic action of Besides their spasmogenic properties, the medicaments of the invention have various interesting pharmacological properties which are indicated in the following table:

Method Animal Doses Manner (3 '-diethylamint mg/kg of propoXyyZ-methadminoxy-3,5dichloistration robcnzenc Gastro-intestinal passage Measured 40 min. after admin- Mouse DE 50 SC. nil effect from istration of the product 0.001 mg/kg to Agent: vegetable charcoal 200 mg/kg Anticmetic activity Measured 30 min. (SC) or 1 hour Dog DE 50 S.C. l6 7( effect with (oral) after administration of 0.25 mg/kg the product. Agent: apomorphine rig/kg SC (atalcptic activity Measured at maximum effect. i.e. Rat DE 50 $.C. 30 .7 effect with from 300 to 360 min. after 200 mg/kg administration of the product. Traction method SC. 197 Measured 30 min. after admin- Mouse DE 50 istration of the product. PI). 40 1; effect with 150 mg/kg Potentialisation of barhituric H. 55.4 narcosis Measured 30 min. after admin- Mouse index istration of the product. 2 P.O. lndex 1.23 with Agent: pentoharbital 0 rug/kg IP 7 200 g/ g Spontaneous moti\'it Winter and LP. 49.1 Measured l5 min. Flataker Mouse DE. 50 HP.) or (10 min. test P.(). effect nil with (P.().) after admin- 200 mg/lg istration of the product. Activograph Mouse DE 50 LP. 16.1-19.7

Method Animal Doses Manner (3-diethylaminomg/kg of propoxy)-2-methadminoxy-3,5-dichloistration robenzenc Antimescaline activity Measured min. after admin- Mouse DE 50 LP. 30 "/1 effect with istration of the product. 100 mg/kg Agent: mesealine 50 mg/kg l.M. Anti-apomorphinc activity (JANSSEN test) Measured 80 min. after admin- Rat DE 50 SC. 3() 7r effect with istration of the product. 600 m /k Agent: apomorphine 1.25 mg/kg I.V. Antimorphine activity (STRAUB test) Measured 60 to I min. after Mouse DE 50 P.O. 313 administration of the product. Agent: morphine 30,rng/kg S.C. Antitremorine activity (CHEN method) Measured 60 min. after admin- Mouse DE 50 LP. 94.7 istration of the product. Agent: tremorine 7.5 mg/kg l.M. Rotating shaft test LP. 71.5

Measured from 10 to 30 min. Mouse DE 50 after administration of the P.O. l8 effect with product. 200 mg/kg Evasion test (KNEIPP method) Measured 1 hour after admin- Mouse DE 50 LP. 75.9 istration of the product. Antiserotonine action v Reduction with respect to Dog DE 50 I.V. 19 reference hypertension caused by serotonine: 'y/kg I.V. f Electrical S.C. 37.1

Anticonvulsant crisis measured Mouse DE 50 activity at peak effect P.O. I43

1 Chemical Agent: l.P. 84.9 Anticon- Crisis Cardiazol Mouse DE 50 vulsant Measured 70 mg/kg P.O. effect nil with activity min. after I.V. 200 mg/kg administration of Agent: the product. Nicotine Mouse DE 50 LP. 31.3

2 mg/kg I.V. P.O. 92.9 Audiogenic crisis l.P. l8 8-19] Anticon- Measured 30 min. after Mouse DE 50 vulsant administration of the P.O. 67 activity product.

Mechanical stimulus Anal- (HAFFNER test) LP. 7l.5 gesic Measured at peak Mouse DE 50 activity effect P.O. :fi: l 79 Chemical stimulus "Anal- (phcnylhcnzoquinone LP. 22 7r effect with I 90 mg/kg gesic test) Mouse DE 50 activity Measured at peak P.O. 30 effect with effect 300 mg/kg Heat stimulus Hot plate S.C. 45 7( effect with Anal (using the JACOB. WOOLFE Mouse DE 50 200 mg/kg gesic and Mac DONALD P.O. :1295 activity method) Measured at peak effect Histaminic hypotension 32 R 50 to 60 7: Anti- 7! reduction with respect l6 R to 55 7/ h R 30 to "/1 histto reference hypotcnsion. Dog 4 I.V. R l() to 30 2 R l() to 25 /r aminic l R l) to l() /1 activity Blockage of the carotid arteries 16 R 35 "/1 X R 32 "/v for 3!) seconds Dog 4 I.V. R 31 '/r reduction with respect 2 R lo "/1 l R (J Orthoto reference hypcr sympa tcnsion. thctic system Adrcnalinc '71 reduction or inversion Dog DE I.V. l2 with respect to reference hypertension. Noradrenalinc '71 reduction with respect Dog DE 50 I.V. l l Orthoto reference hypertension sympathctic Nicotine lo R 4 .4 X R 13 encc hypotcnsion 9 Method Animnl Doses Munncr (3 '-dicthyluminomg/kg propox y )-2-methadminuxy-3.5-tlichloistrution ruhcnzcnc system 7r reductiuon with respect 4 |.V. R m 3 7: to reference hypcr- Dog 2 R 0 V: l R 13 "/1 tension. Acctylcholinc 16 R I 33 Z 8 R 37 9i 9; reduction with Dog 4 IV R 7r respect to rcfcr- 2 R 5 '7: l R 0 Paracncc hypotcnsion sympathctic Vngal Excitation 16 R l '1? 8 R 2i "k system 'lr reduction with Dog 4 IV R l A respect to rcfcr- 2 R 0 The experimental results were confirmed in clinics compressed tablets or phials of a pharrnacologically acceptable salt.

What is claimed is:

l. A dialkylaminoalkyl ether of 2-alkoxy-3,5- dihalobenzene, a non-toxic acid addition salt thereof or a quaternary ammonium salt thereof, said dialkylaminoalkyl ether of 2-alkoxy-3,S-dihalobenzene having the formula:

in which m is an integer from 0 through 2; and n is an integer from 0 through 2; R is hydrogen or lower alkyl of less than 6 carbon atoms; R is lower alkyl of less where the products were administered in the form of 2 4. A compound of claim 1 which is (3'- diethylaminopropoxy)-2-methoxy-3,5- dichlorobenzene hydrochloride.

5. A compound of claim 1 which is (3'- morpholinopropoxy )-2-methoxy-3,S-dichlorobcnzene hydrochloride.

6. A compound of claim 1 which is (2-diethylaminol -methyl-ethoxy)-2-methoxy-3,S-dichlorobenzene oxalate.

7. A compound of claim 1 which is (3- diethylaminopropoxy )-2-methoxy-3 ,5- dichlorobenzene bromomethyllate.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent 3,904,622 Dated September 9, 1975 Michel Leon Thominet Inventor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 18, heateed" should read heated A line 57, "aceton" should read acetone Column 8,

change the symbol (3 occurrences) to read 7 7 Claim 1, the formula should appear as shown below:

Signed and Scaled thisthirtieth D f March 1976 [SEAL] A ttes t:

RUTH C. MASON C. MARSHALL DANN Arresting Officer (mnmissinner uj'lalents and Trademarks 

1. A DIALKYLAMINOALKYL ETHER OF 2-ALKOXY-3,5-DIHALOBENZENE, A NON-TOXIC ACID ADDITION SALT THEREOF OR A QUATERNARY AMMONIUM SALT THEREOF, SAID DIALKYLAMINOALKYL ETHER OF 2ALKOXY-3,5-DIHALOBENZENE HAVING THE FORMULA
 2. A compound of claim 1 which is (2''-diethylaminoethoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 3. A compound of claim 1 which is (3''-dimethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 4. A compound of claim 1 which is (3''-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 5. A compound of claim 1 which is (3''-morpholinopropoxy)-2-methoxy-3,5-dichlorobenzene hydrochloride.
 6. A compound of claim 1 which is (2''-diethylamino-1''-methyl-ethoxy)-2-methoxy-3,5-dichlorobenzene oxalate.
 7. A compound of claim 1 which is (3''-diethylaminopropoxy)-2-methoxy-3,5-dichlorobenzene bromomethylate. 